Proteins
are far more active and dynamic than scientists have
imagined, say researchers at the University of Pennsylvania
School of Medicine.

Their study, to be published Thursday in the journal
Nature, affords the first comprehensive view scientists
have had of a protein's internal motion.

"The interior of a protein is much more liquid-like
than scientists originally anticipated. Everything is
moving, and it's moving all the time, very fast,"
said A. Joshua Wand, PhD, Professor of Biochemistry
and Biophysics at Penn and principal author of the study.

"The really exciting thing is they move so much
that, potentially, it dramatically influences how they
work," Wand said. "This is the beginning of
a long new story that, fundamentally, will have a lot
to do with understanding protein function."

Wand and his colleague used nuclear magnetic resonance
(NMR) relaxation imaging to track the activity of the
calmodulin-peptide protein complex across a spectrum
of 13 temperature settings that ranged from 278 degrees
Kelvin to 346 degrees Kelvin (from 15 degrees Celsius
to 73 degrees Celsius). The NMR data demonstrate that
a much larger range of internal motion is present in
calmodulin than crystallographic studies -- the standard
method of discerning protein properties -- have had
the capacity to demonstrate.

"The beauty of this experimental study is that
motion and temperature are inextricably linked, and
by understanding how motion changes in response to temperature,
you understand
more about the motions themselves," said Andrew
Lee, PhD, a researcher who worked on the study with
Wand at Penn as a postdoctoral fellow before taking
a faculty position at the University of North Carolina.
He added: "The common thinking has been that the
structure of proteins dictates their functions, and
that each one has a different biochemical task. But
they aren't static structures -- they fluctuate, and
that these fluctuations are also critical for protein
activity."

In their research, Wand and Lee found the calmodulin
protein has three distinct bands (or preferred magnitudes)
of motion on a subnanosecond time scale, a richness
of variation that was not previously known. Further,
when they compared those findings with existing data
on other proteins that had been studied at single temperatures,
Wand and Lee discovered the same spectrum of motion.
This suggests that the range of motion is a general
fundamental property of proteins.

According to Wand, the research findings also suggests
an explanation for the "glass transition"
characteristic of proteins -- the feature that makes
proteins respond to heat in the same fashion as glass.
(The onset of dynamics in the glass transition is often
associated with the attainment of biological activity.)

"The key word is 'entropy' -- the ability to assume
multiple states," Wand said. "For a long time,
people assumed proteins didn't have significant entropy,
so they discounted its potential functional role. In
fact, proteins have a lot more ways to accomplish their
functions than we realized. This dynamism has central
significance for how proteins may work."

"People tend to think of proteins as static, because
they see pictures of them as snapshots. But now scientists
will have to start considering the effects of entropy
and dynamics," Lee added.

The new, more dynamic picture of proteins also offers
a new direction for pharmaceutical companies that may
eventually enable them to enhance the effectiveness
of drugs by targeting more accessible protein sites,
Wand said. The research was funded by the National Institutes
of Health.